The major goal of this research project is to identify and characterize genes involved in the pathogenesis of human kidney cancer. Our major accomplishments this year are: 1. We have continued our studies of families with an inherited predisposition to develop papillary renal carcinoma. In our studies of European families with papillary renal carcinoma, we identified 3 Northern Italian families with papillary renal carcinoma and identical germline mutations in the MET proto-oncogene. This observation suggests that these 3 Northern Italian families shared a common ancestor who had a germline mutation in the MET gene. We studied a remarkable Hungarian family with papillary renal carcinoma and an inherited tendency to develop extra breast tissue. We identified a germline MET mutation in this Hungarian family. It is clear that this MET mutation predisposes to papillary renal carcinoma in this family. At this time, it is uncertain whether the mutation in MET predisposes to the development of extra breast tissue. We demonstated that mutations in the MET gene predispose to a specific histologic type of papillary renal carcinoma. There are two different histologic types of papillary renal carcinoma. Patients with mutations in the MET gene are predisposed to papillary renal carcinoma type 1. 2. We continued our studies of a rare inherited tumor of the kidney that we previously had named "familial renal oncocytoma". We observed that members of families affected with renal oncocytoma also were affected with tumors of the hair follicle, called fibrofolliculomas. Fibrofolliculomas are the cardinal feature of a previously described inherited disorder - the Birt Hogg Dube syndrome. We wrote to Dermatologists in the United States and Canada to recruit families with members affected with fibrofolliculomas (Birt Hogg Dube syndrome). So far, we have identified 18 families with this syndrome including the family originally described by Drs. Birt, Hogg and Dube in 1977. We have collected blood samples and skin biopsies from family members in preparation for an effort to identify the Birt Hogg Dube (BHD) gene. Of particular interest, patients with fibrofolliculomas appear to be at increased risk for the development of kidney tumors and spontaneous collapse of the lungs. 3. Our work on the development of a mouse model for VHL is progessing. We have prepared chimeric mice composed of two populations of cells. One population of cells is normal; the other cell population contains one copy of the VHL gene surrounded by lox P sites (2 zippers), and the other copy of the VHL gene that is normal. Work is underway to produce chimeras with one cell population without a functional VHL gene. These chimeras will be studied carefully to see whether tumors or other alterations have been produced. We are in the midst of preparing mice that will mimic human VHL disease; these mice will have one inherited mutation and one acquired mutation in the VHL gene.